ORIGINAL ARTICLE

Pediatrics Sciences Journal (PedScij) 2023, Volume 4, Number 2: 54-59

P-ISSN: 2722-0427, E-ISSN: 2722-1474

Comparison efficacy and safety sodium valproate

versus combination sodium valproate and
Published by
levetiracetam for treatment epilepsy in children:
Pediatrics Sciences Journal
a meta-analysis

Detria Rahma Gasti1*, Aulia Sita Hapsari1, Karima Iffani2

ABSTRACT

Background: The most prevalent severe neurological condition, impacting more than 50 million individuals globally, is
epilepsy. A new anti-epileptic drug (AED) called levetiracetam (LEV) has shown promise as an adjuvant treatment for children’s
treatment-resistant partial-onset seizures. Sodium valproate (SV) is a commonly used anti-epileptic medication that has a
range of effects and a distinct mode of action. Combining LEV and SV has emerged as a viable clinical treatment plan. This
study aimed to use meta-analysis to estimate the safety and effectiveness of LEV with SV in pediatric epilepsy patients.
Methods: From January 1993 to April 2023, the Cochrane Library, PubMed, and ScienceDirect were searched. The included
literature consisted of randomized controlled clinical trials that examined the use of SV in conjunction with LEV in pediatric
epileptic patients. This meta-analysis followed the PRISMA guidelines. The statistical program used for the meta-analysis was
1
dr. Soepraoen Army Hospital, Malang Revman V.5.4.1.
Indonesia; Results: From 568 original titles screened, data were extracted from 3 studies (n=303). Compared with SV alone, SV combined
2
Department of Paediatrics, dr.
with LEV significantly improved the overall therapeutic effect of epilepsy (OR=0.80; 95%CI= 0.72-0.89; p<0.0001). The
Soepraoen Army Hospital, Malang
Indonesia. observation group significantly reduced the occurrence of adverse drug reactions (ADRs) of nausea and vomiting (OR=2.77;
95%CI=1.08-7.09; p=0.03).
*Corresponding to: Conclusion: According to this meta-analysis, SV plus LEV considerably increased the overall therapeutic effect of epilepsy
Detria Rahma Gasti; while concurrently lowering the incidence of ADRs when compared to SV alone. Thus, for treating epilepsy in children, we
dr. Soepraoen Army Hospital, Malang advise SV in conjunction with LEV.
Indonesia;
detriarahmagasti@gmail.com Keywords: levetiracetam (LEV), sodium valproate (SV), epilepsy, efficacy, safety, children.
Cite This Article: Gasti, D.R., Hapsari, A.S., Iffani, K. 2023. Comparison efficacy and safety sodium valproate versus
Received: 2022-09-08 combination sodium valproate and levetiracetam for treatment epilepsy in children: a meta-analysis. Pediatrics Sciences
Accepted: 2023-11-12
Journal 4(2): 54-59. DOI: 10.51559/pedscij.v4i2.54
Published: 2023-12-05

INTRODUCTION
The most prevalent severe neurological
condition, impacting more than 50
million individuals globally, is epilepsy.1
Uncontrolled seizures affect 30% of
people, which has been linked to mental
disease and a poor quality of life.2 The
likelihood of having a single epileptic
seizure in one’s lifetime is 10%. The most
frequent causes of seizures in children are
hereditary, prenatal damage-related injury,
and anomalies of cortical development.3
The International League Against
Epilepsy (ILAE) Task Force developed the
operational (practical) clinical definition
of epilepsy, which is defined as a brain
disease indicated by any of the following
conditions: one unprovoked (or reflex)
seizure and a probability of additional
seizures equal to or greater than the general
recurrence risk (at least 60%) following
two unprovoked seizures that occur over
the following ten years.4 Additionally,
several studies have shown that youngsters
experience epilepsy more frequently than
adults.5 In the course of epileptogenesis,
overexcited neurons in the vicinity of
the lesion produce paroxysmal aberrant
high-frequency discharges that spread
to the surrounding tissue, resulting in
rapid, transitory, and recrudescent brain
dysfunction.6 Pediatric epilepsy frequently
results in significant neural damage
due to the insufficient development of
children’s central nervous systems, which
may lead to other neurological diseases
in children, such as strokes. In the most
severe situations, mental retardation can
happen, causing significant brain damage
to the kid and adding to the load on the
family and society.7 There are currently
no agreed-upon guidelines for the clinical
management of pediatric epilepsy.8
Therefore, one of the main therapeutic
tasks is to investigate safe and effective
therapies for pediatric epilepsy.9
Valproate, a first-line broad-spectrum
anti-epileptic drug (AED), is believed to
offer protection against a range of seizure
types.10 One of the most adaptable and
powerful AED is valproate.11 Treatment
for absence, myoclonic, partial, and
tonic-clonic seizures is successful with
valproate.12 After an oral dose, valproate
is effectively absorbed, with bioavailability
exceeding 80%. Two hours are needed to
see peak blood levels. If a medication is
taken after a meal, food may help to increase
tolerability and delay absorption.13 The

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Open access: 54-59 | 10.51559/pedscij.v4i2.54
https://pedscij.id/index.php/pedscij
 ORIGINAL ARTICLE

most frequent side effects of valproate that

are dose-related include nausea, vomiting,
and other gastrointestinal problems such
as heartburn and stomach discomfort.14
To prevent these adverse effects, the
medication should be taken gradually. At
higher levels, a slight tremor is frequently
noticed. Some patients experience
reversible side effects, including weight
gain, increased hunger, and hair loss.
Patients under the age of two and those
taking various drugs are most in danger.15
One of the most commonly suggested
treatments for epilepsy is the broad-
spectrum AED Levetiracetam (LEV).16
This is primarily because of its perceived
low risk of side effects, wide therapeutic
window, excellent pharmacokinetics, and
lack of drug-drug interactions.17 Treatment
of myoclonic, partial, and tonic-clonic
seizures with LEV is beneficial. 20–40 mg/
kg/day of oral maintenance medication
for children with therapeutic values of
6–20 mg/L.18 LEV side effects include
drowsiness, asthenia, ataxia, infection
(colds), and ataxia.19 Extended-release pills
are one type of oral formulation, and an
intravenous preparation is also offered.20 Figure 1. The PRISMA about the study search, selection, and inclusion process.
Sodium valproate (SV) is traditionally
used to treat epilepsy, although there included in the search, presented in Figure Assessment of study quality
are worries regarding its adverse effects 1. We used the Jadad score, an evaluation of
and teratogenicity. LEV is generally well the Jadad score based on accessible criteria
tolerated and has a substantially lower risk Inclusion and exclusion criteria from studies at the Oxford Center for
of teratogenicity. LEV is, therefore, now The inclusion characters of the articles Evidence-Based Medicines, to determine
preferred, especially for girls and women, used in this analysis were (1) randomized the quality of the publications that
since treatment for epilepsy is frequently control trials (RCTs), (2) a combination satisfied the inclusion criteria. The article
ongoing.21 Clinical professionals may of LEV and SV, and (3) the article at least is considered good quality if the value is
find this valuable information in light includes the results of reducing adverse greater than 4. The score ranges from 0 to
of the previously mentioned statistics drug reactions. References will be excluded 5. A study with a 3–4 score is considered
and the large number of recent trials. if the article is an editorial, case report, average quality. When the score is less
We conducted a systematic review and or review article, and all references other than 3, it is considered low quality.23
meta-analysis to compare the efficacy and than RCTs; Libraries that do not report
safety of SV alone vs. SV plus LEV in the the results of the adverse drug reactions of Statistical analysis
treatment of pediatric epilepsy. the combination of LEV and SV; data that Review Manager version 5.4.1 is used in
are incompatible and cannot be extracted/ this study’s statistical analysis. The odds
METHODS processed are also excluded. The author ratio is computed using a 95% confidence
Literature search did the screening readings, pulled the interval (CI) because the data measurement
PRISMA recommendations form the basis data, and collected all the results and side is dichotomous (OR). We also calculated
of our meta-analysis.22 The Cochrane, effects of the drugs. the heterogeneity distribution in each trial
ScienceDirect, and PubMed search pages using the Cochrane Chi-Square test and
were utilized to find the libraries. LEV, SV, Outcome assessed inconsistency (I2); if the p-value is less
epilepsy, and efficacy and safety in treating The effectiveness of the combination of than 0.05, it is considered significant. The
epilepsy patients in children were included LEV and SV in treating children with study’s heterogeneity is substantial if the
as keywords. All libraries with randomized epilepsy was one of the parameters inconsistency value (i2) is > 50%.
controlled trials, which covered the period we observed, as was the safety of the
from January 1993 to April 2023, were combination in decreasing side effects.

Published by Pediatrics Sciences Journal | Pediatrics Sciences Journal 2023; 4(2): 54-59 | 10.51559/pedscij.v4i2.54 55
 ORIGINAL ARTICLE

Table 1. Characteristics of study quality and articles

Study Jadad Case (n)
Article Intervention Country LE
Design Score SV Combination SV and LEV
Chen 2021 SV vs. combination SV and LEV China RCT 1b 3 40 43
Liu 2019 SV vs. combination SV and LEV China RCT 1b 3 50 50
Zhao 2019 SV vs. combination SV and LEV China RCT 1b 3 60 60
LE: Level of Evidence Base; RCT: Randomized Control Trial

Figure 2. Forest plots of the efficacy based on RR for overall therapeutic effect.

Figure 3. Forest plots of the efficacy and safety of a combination of SV and LEV based on OR for ADR nausea and vomiting.

Figure 4. Forest plots of the efficacy and safety of a combination of SV and LEV based on OR for ADR dizziness.

RESULTS
Literature screening process and
results
We identified 568 possibly relevant studies.
Three trials met the prospective inclusion
criteria and were included in our meta-
analysis.
Study characteristics
A total of 303 patients were included
in three studies. All of the studies
were published in 2019 and 2021. For
these studies, 40 was the minimum,
and 60 was the maximum number of
participants. Only SV was administered
as the control group in one of the three
RCTs; the other two used either SV or
SV plus topiramate.24,25,26 With regard to
interventions, all 3 RCTs combined SV
with LEV. The characteristics of each study
are shown in Table 1.
Efficacy therapeutic effect
Data on the overall therapeutic effect were
provided by all three trials (n = 303). The
application of SV combined with LEV
in the treatment of pediatric epilepsy
significantly improved the efficacy
therapeutic effect (OR=0.80; 95%CI=0.72-
0.89; p <0.0001) with high heterogeneity
I2=12%, as compared with SV alone or
SV combined with topiramate. Figure 2
illustrates this finding.
Adverse event
Nausea and Vomiting
Three studies reported decreasing side
effects of nausea in combination with SV
and LEV (OR=2.77; 95%CI=1.08-7.09;
p=0.03) with high heterogeneity I2=12%,
as shown in Figure 3.

56 Published by Pediatrics Sciences Journal | Pediatrics Sciences Journal 2023; 4(2): 54-59 | 10.51559/pedscij.v4i2.54

Figure 5. Forest plots of the efficacy and safety of combination SV and LEV based on OR for ADR diarrhea and gastrointestinal
reactions.
Dizziness
In two studies in pooled analysis with 100
patients in the SV group and 103 patients
in combination SV and LEV group,
no significant difference was reported
(OR=1.59; 95%CI=0.44-5.83; p=0.48)
with no heterogeneity I2=0% mis shown in
Figure 4.
Diarrhea and Gastrointestinal Reaction
Investigators reported a gastrointestinal
tract problem and diarrhea in two
studies, showing no significant difference
(OR=1.58; 95%CI=0.43-5.82; p=0.49)
with no heterogeneity I2=0%, as shown in
Figure 5.
DISCUSSION
Epilepsy is a problem in developing
nations.27 One of the chronic brain
problems that affects people of all ages,
including children, is epilepsy. Although
the AED can be prescribed alone
(monotherapy) or in combination with
other medications (polytherapy), using
a single medication is generally advised
when treating epilepsy when considering
the risk-benefit ratio in patients, especially
in pediatrics.28 Asia is home to more
than half of the 50 million epileptics
worldwide, according to estimates.29
One of the most prevalent neurological
conditions in Indonesia, particularly in
young children under the age of five.30 A
neurological condition known as epilepsy
is brought on by irregular brain nerve
activity that results in recurrent seizures.31
The incidence is 114 per 100,000 people
annually. In contrast to industrialized
nations, there are between 24 and 53
incidences of epilepsy per 100,000 people
per year in poor nations.32
One of the most often prescribed AEDs
in clinical practice is SV, a broad-spectrum,
Published by Pediatrics Sciences Journal | Pediatrics Sciences Journal 2023; 4(2): 54-59 | 10.51559/pedscij.v4i2.54
highly selective agent.33 However, if SV
is the only medication used, it might
be challenging to control the condition
completely.34 Meanwhile, the liver breaks
down SV, potentially harming a child’s
liver function.35 Additionally, the anti-
seizure treatment process is challenging,
and several side effects tend to exacerbate
the pain of the medication, decreasing
children’s adherence to the medication
and producing unsatisfactory results.36
One of the most promising anti-seizure
medications is LEV, which also has an
excellent pharmacokinetic profile, few
drug interactions, and a novel mechanism
of action.37 An entirely unique mechanism
for LEV’s action has never been mentioned
in any other anti-seizure medication.38
Recent preclinical studies suggest that
LEV, especially when combined with SV,
may have an extra therapeutic advantage
due to its enhanced protective function.39
Compared to all other clinically used
combinations of anti-seizure medications,
LEV shows a clear and significant
enhancement of the anticonvulsant effect
of SV.40
In contrast to SV alone or SV combined
with topiramate, the application of SV
combined with LEV in the treatment
of childhood epilepsy can significantly
improve the efficacy of therapeutic effects
while at the same time reducing the
occurrence of adverse reactions, according
to the findings of this meta-analysis.24
LEV and SV together show that these two
broad-spectrum epilepsy medications do
not increase patients’ sensitivity to them
but rather increase their effectiveness.41
A critical review of several preclinical
trials involving levetiracetam and other
anticonvulsants in combination therapy
for different seizure and epilepsy models
is presented in this report. Levetiracetam
ORIGINAL ARTICLE
typically amplifies the protective effects
of a wide range of clinically used AEDs
or other anticonvulsants; valproate was a
particularly popular AED in this context.42
Different drug doses, combinations, and
inter-individual variability can all affect
blood drug levels. In order to ensure
that the blood level of the medication is
within the therapeutic range, the dosage
setting and frequency of administration
must be taken into account. The medicine
often will not have a therapeutic impact if
levels are below the minimally adequate
level. Contrarily, drug toxicity symptoms
typically manifest if the drug’s level in
the blood surpasses the lowest toxicity
limit. Combinations in the therapeutic
regimen can also significantly affect drug
levels.43 Conversely, levetiracetam and
valproate combinations significantly
raised the therapeutic index, calculated
as the difference between the toxic
dose of 50% (TD50) and the effective
dose of 50% (ED50). Additionally, when
levetiracetam was observed to enhance
the anticonvulsant effects of other
medications, the therapeutic index was
significantly higher. Levetiracetam was
administered concurrently with plasma
and brain AED concentrations. However,
this had no effect. The lone exception was
SV, but its plasma and brain concentrations
were decreased when levetiracetam was
also administered.42 This combination is
more effective and reduces the side effects
of nausea and vomiting due to the lowered
plasma and brain concentrations.
Furthermore, according to two
studies, using LEV and SV together can
lessen patients’ symptoms of nausea and
vomiting; other studies also explained
that the combination of valproic acid and
LEV reduced the side effects of nausea
and vomiting.44 Based on the data above,
57
 ORIGINAL ARTICLE
nausea and vomiting can significantly
decrease when SV is combined with LEV.
There are some limitations in this study.
First, only three RCTs were included;
additional RCTs are needed to confirm
our findings. Second, the outcomes of the
included trials were not all the same, but
the clinical efficacy was significant enough
to compare the relative superiority of the
therapy. Finally, due to the small sample
and race of the individuals, it may not have
been able to identify significant differences
across the various groups.
CONCLUSION
This meta-analysis study demonstrated
the combination of SV and LEV to be
significantly effective. Nausea and vomiting
are side effects that have diminished when
SV and LEV are combined.
ETHICAL APPROVAL
Not applicable.
CONFLICT OF INTERESTS
The authors declare that there is no conflict
of interest.
FUNDING
None.
AUTHOR CONTRIBUTIONS
DR: concepts, design, definition of
intellectual content, literature search, data
analysis, statistical analysis, manuscript
preparation, manuscript editing,
manuscript review, guarantor. AS: data
analysis, statistical analysis, manuscript
editing. KI: definition of intellectual
content, literature search, manuscript
preparation, manuscript editing.
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